Background

The genus Providencia includes urease-producing gram-negative bacilli that are responsible for a wide range of human infections. Although most Providencia infections involve the urinary tract, they are also associated with gastroenteritis and bacteremia.[1] Providencia infections are uncommon and are usually nosocomial. They represent an emerging problem because of the increasing prevalence of antibiotic resistance secondary to extended-spectrum beta-lactamase (ESBL).

The first species of the genus now known as Providencia was isolated by Rettger in 1904. The bacterium was initially seen in chickens in what was believed to be an epidemic of fowl cholera. The bacterium was not further characterized until 1918, when it was named Bacterium rettgerii by Hadley et al. Organisms belonging to the genus Providencia have undergone many taxonomic changes since their first description, with frequent confusion and overlap between organisms of the closely related genera Providencia,Proteus, and Morganella.

Kauffmann first proposed the genus name Providencia in 1951, referring to a group of organisms studied by Stuart and colleagues at Brown University in Providence, Rhode Island. By 1983, the 4 species in the Providencia genus at that time were fully differentiated with DNA hybridization and urea hydrolyzation. In 1986, Providencia heimbachae was the fifth species discovered.[2]

The 5 species currently in the genus Providencia, in descending order of prevalence, include Providencia stuartii, Providencia rettgeri, Providencia alcalifaciens, Providencia rustigianii, and P heimbachae.[3]

Pathophysiology

Providencia species are found in multiple animal reservoirs, including flies, birds, cats, dogs, cattle, sheep, guinea pigs, and penguins, and are resident oral flora in reptiles such as pythons, vipers, and boas. Providencia species are also found commonly in soil, water, and sewage. Examples of Providencia infections in animals include neonatal diarrhea due to P stuartii infection in dairy cows and enteritis caused by P alcalifaciens infection in dogs. P rettgeri has been isolated in crocodiles with meningitis/septicemia and in chickens with enteritis.[4] P heimbachae has been isolated in penguin feces and an aborted bovine fetus.[5]

In humans, Providencia species have been isolated from urine (most common), stool, and blood, as well as from sputum, skin, and wound cultures. P stuartii septicemia is primarily of urinary origin. One case study has described P stuartii as the etiology of infective endocarditis.[6] Another case report found P rettgeri to be a cause of ocular infections, including keratitis, conjunctivitis, and endophthalmitis.[7]

P stuartii is frequently isolated in patients with indwelling urinary catheters and is known to persist in the urinary tract after bladder access is attained. In one study, the mean duration of bacterial colonization was 6.4 months.[8] The persistence of bacteria in the urinary tract is thought to be due to an adhesin, mannose-resistant/Klebsiella -like (MR/K) hemagglutinin, which allows bacteria to adhere to urinary catheters (mediated by 3 fimbriae).[8, 9] In a 1994 study by Rahav et al, persistence patterns in males and females were found to differ, with P stuartii showing more persistence in females. Reasons theorized include different receptor characteristics in male and female urinary tracts and a bacterial predilection for Foley catheters over condom catheters, which are used more commonly in males.[8]

ESBL-positive P stuartii is an increasing problem in hospitalized patients. In one study, 52% of 223 P stuartii isolates were found to be positive for ESBL in a hospital population that included ICU, medical, and surgical wards over a 4-year span.[10]

P alcalifaciens, P rettgeri, and P stuartii have been implicated in gastroenteritis. In one study, P rettgeri and P stuartii were found to be highly invasive using in vivo testing with Caco-2, a human colon carcinoma cell line. However, a common virulence plasmid was not identified in Providencia species.[11, 12] Providencia species, most commonly P agalactiae, have been demonstrated in the stool of symptomatic patients, although testing protocols used to identify diarrheagenic bacterial pathogens do not generally include Providencia.

Epidemiology

Frequency

United States

P stuartii and, to a lesser extent, P rettgeri are the most common Providencia species that cause human infection. While uncommon in most clinical settings, these organisms tend to cause cystitis in patients with bladder catheters and are primarily associated with complicated urinary tract infections. In a Canadian study in 2001, Providencia species were isolated in 18% of complicated urinary tract infections.[13] In contrast, Providencia bacteriuria in acute hospital settings is rare (0.3-1%).[8]

The prevalence of Providencia infections are generally low, although it is increasing. More significantly, Providencia infections with antimicrobial resistance patterns are increasing. In 2003, a study at an Italian university hospital with medical, surgical, and intensive care units found that the prevalence of ESBL-producing P stuartii in the general patient population increased from 31% in 1999 to 62% in 2002. Over a 4-year span, P stuartii was isolated in 0.08% of patients. Of these isolates, 87% were found in urine, 10% in blood, and 3% in respiratory tract secretions.[10]

P stuartii is most often found in complicated urinary tract infections in patients with chronic indwelling urinary catheters or condom catheters. Providencia species are rarely a cause of uncomplicated urinary tract infections. In a study of patients with urinary catheters living in a retirement home, P stuartii was the most commonly isolated bacteria, found in 59% of urine specimens. (The next most common was Escherichia coli, at 32%.)[8]

Providencia species, specifically P alcalifaciens and P rettgeri, have also been shown to be an infrequent cause of foodborne gastroenteritis. In 1996, a large outbreak of foodborne P alcalifaciens infections occurred in Japan at multiple schools, affecting student and teacher populations.[14] This was the first reported outbreak of foodborne P alcalifaciens gastroenteritis. Providencia species, especially P rettgeri, have also been implicated as cause of traveler’s diarrhea. In a Japanese study, 130 patients with diarrhea were evaluated at the Kansai Airport quarantine station, and Providencia species were isolated in 15.4% of stool samples. Most travelers who reported diarrhea had traveled to Southeast Asia.[11]

International

Providencia species are found worldwide. A study that examined ESBL-producing Enterobacteriaceae distribution worldwide (including Providencia species) found that the prevalence of ESBL-positive bacteria varied across geographical boundaries. The highest percentage of ESBL-positive isolates as found in Latin America (44%) and the lowest in Netherlands and Germany (2% and 2.6%, respectively).[15] . Another multidrug-resistant outbreak of Providencia stuartii was reported in Greece in 2012.[16]

Mortality/Morbidity

The mortality rate in patients with Providencia bloodstream infection ranges from 6-33%. The rate is greater in polymicrobial infection.

Race

All races appear to be equally susceptible to Providencia infection.

Sex

Males and females appear to be equally susceptible to Providencia infection. In one study, however, a significant difference was seen in the persistence pattern of bacteriuria in women versus men among nursing-home patients with long-term urinary catheterization (88.25% vs 50.5%).[8]

Age

Elderly persons are at much greater risk of P stuartii or P rettgeri infection, most likely because these infections are associated with the use of indwelling urinary catheters, which are more common used in elderly populations.

P alcalifaciens gastroenteritis has been documented in children and adults. In a 2005 study, a large outbreak of gastroenteritis was found to be attributable to P alcalifaciens infection. The outbreak involved students and teachers of two kindergartens and one high school. The prevalence of infection was higher in children (53% of kindergartners affected vs 36% of adult teachers).[14] Another study demonstrated that P rettgeri infection is a potential cause of traveler's diarrhea in adults.[11]

Both species (P rettgeri more commonly than P stuartii) have recently been implicated as etiologic agents in traveler's diarrhea, making travel history important in patients with acute-onset diarrhea.

Vomiting is common in P rettgeri gastrointestinal infection.

Patients with respiratory tract infection are more likely to have been intubated or to have undergone intratracheal suctioning. These conditions promote airway colonization. Presenting symptoms are those typical of pneumonia, including cough and fevers/chills.

Patients with burns are at a higher risk of Providencia wound infection.

Infections with these Providencia species are most likely to elicit gastrointestinal symptoms. In a study that examined P alcalifaciens infection specifically, the most common presenting symptom was diarrhea (86.7%), followed by abdominal pain (77.8%) and fever greater than 37.5°C (24.1%). Diarrhea was described as watery; no bloody diarrhea was reported.[14, 17]

Laboratory Studies

Obtain bacterial Gram stain and culture from the suspected site of infection.

In a patient who requires hospitalization for suspected infection or in whom a bloodstream infection is suspected, obtain two sets of blood cultures from different sites.

Obtain urinalysis/urine culture in patients with suspected urinary tract infection. The presence of white cells or leukocyte esterase may help to distinguish urinary tract colonization from infection.

CBC count is used to monitor for leukocytosis or a left shift, which indicates infection. A chemistry panel is used to monitor renal function and complications or toxicities associated with antibiotics.

Once an organism has been identified, susceptibility testing is extremely important to narrow therapy.

Other Tests

Medical Care

Antimicrobial Therapy

Medical care of Providencia infection includes initiation of an antimicrobial agent to eradicate infection. Selection of an empirical agent (while awaiting microbiological identification of the organism and susceptibility testing) should be based on known resistance patterns in the patient's locality (eg, community, hospital, long-term care facility). Once the species of the infecting Providencia pathogen has been identified (but before susceptibilities are available), selection of an empiric antimicrobial agent can be based on known patterns of susceptibility across species, as detailed below.

Generally, Providencia species are almost always resistant to tetracyclines, older penicillins, and cephalosporins, with susceptibility to late-generation cephalosporins, aztreonam, imipenem, and meropenem. Providencia species have variable susceptibilities to fluoroquinolones, aminoglycosides, and trimethoprim-sulfamethoxazole (TMP-SMX).

P stuartii is typically the most resistant of all Providencia species. A 2006 Italian study found that ESBL-positive P stuartii made up 10% of all ESBL species and had marked resistance to amoxicillin-clavulanate (81.8%), ampicillin-sulbactam (40.1%), gentamicin (79.5%), and ciprofloxacin (84.1%). In another study, 53% of P stuartii strains isolated were found to produce ESBL.[10]

Carbapenems are the best choice for empirical therapy in life-threatening infections or nosocomial outbreaks suspected to be caused by P stuartii until speciation is confirmed.

Amikacin and beta-lactam/beta-lactamase inhibitors such as piperacillin/tazobactam are good first-line agents in non–life-threatening infections.[15]

P alcalifaciens and P rustigianii tend to be the most susceptible of the Providencia species. Although often resistant to tetracyclines, older penicillins, and cephalosporins, they are usually susceptible to TMP-SMX, fluoroquinolones, aminoglycosides, late-generation cephalosporins, aztreonam, and carbapenems.

P rettgeri tends to fall between the two groups mentioned above with regard to its susceptibility profile.

Once the identity of the pathogen and its susceptibility profile are known, target therapy with the most narrow-spectrum agent to which the organism is susceptible.

Duration of therapy should range from 1-3 weeks, depending on the site of infection (14 d for bacteremia; 14-21 d for complicated or catheter-associated urinary tract infection).

Catheter Removal

If infection is associated with an indwelling device (eg, urinary catheter), remove the catheter. Carefully evaluate the continued need for the catheter. If its use continues to be required, insert a new catheter. If not, discontinue use of the catheter.

Aztreonam (Azactam)

Clinical Context:
A monobactam (not a beta-lactam) antibiotic that inhibits cell wall synthesis during bacterial growth. Active against gram-negative bacilli but very limited gram-positive activity and not useful for anaerobes. Lacks cross-sensitivity with beta-lactam antibiotics. May be used in patients allergic to penicillins or cephalosporins.

Duration of therapy depends on severity of infection and should be continued for at least 48 h after symptoms resolve asymptomatic or evidence of bacterial eradication obtained. Doses smaller than indicated should not be used.

Transient or persistent renal insufficiency may prolong serum levels. After initial loading dose of 1 or 2 g, reduce dose by one half for estimated ClCr of 10-30 mL/min/1.73 m2. When only serum creatinine concentration available, the following formula (based on sex, weight, and age) can approximate ClCr. Serum creatinine should represent a steady state of renal function.

Maintenance dose is one fourth of usual initial dose given at usual fixed interval of 6, 8, or 12 h.

For serious or life-threatening infections, supplement maintenance doses with one-eighth of initial dose after each hemodialysis session.

Elderly persons may have diminished renal function. Renal status is a major determinant of dosage in these patients. Serum creatinine may not be an accurate determinant of renal status. Therefore, as with all antibiotics eliminated by kidneys, obtain estimates of ClCr and make appropriate dosage modifications. Insufficient data are available regarding IM administration to pediatric patients or dosing in pediatric patients with renal impairment. Administer IV only to pediatric patients with normal renal function.

Ceftazidime (Ceptaz, Fortaz, Tazicef, Tazidime)

Clinical Context:
Third-generation cephalosporin with broad-spectrum, gram-negative activity, including pseudomonas; lower efficacy against gram-positive organisms; higher efficacy against resistant organisms. Arrests bacterial growth by binding to one or more penicillin-binding proteins, which, in turn, inhibit the final transpeptidation step of peptidoglycan synthesis in bacterial cell wall synthesis, thus inhibiting cell wall biosynthesis. The condition of the patient, severity of the infection, and susceptibility of the microorganism should determine the proper dose and route of administration.

Cefotaxime (Claforan)

Clinical Context:
Third-generation cephalosporin with broad gram-negative spectrum, lower efficacy against gram-positive organisms, and higher efficacy against resistant organisms. Arrests bacterial cell wall synthesis by binding to one or more of the penicillin-binding proteins, which in turn inhibits bacterial growth. Used for septicemia and treatment of gynecologic infections caused by susceptible organisms.

Class Summary

Selection of empiric antimicrobial therapy must take into account the likely pathogens given the clinical setting. Selection of final antimicrobial therapy, once the identity of the infecting organism is known, should favor the safest and most cost-effective agent with the narrowest spectrum of activity to which the infecting pathogen is susceptible.

Further Outpatient Care

Monitor the patient for resolution of clinical manifestations and potential toxicities of antibiotics.

Infection may recur, particularly if an indwelling device remains in place. If repeat cultures after treatment continue to demonstrate the organism, clinical evidence of infection should be sought. The urine may continue to be colonized after a course of antibiotic treatment, especially in the presence of an indwelling device (eg, urinary catheter, condom catheter).

Transfer

If a patient is being transferred to another medical institution (eg, skilled nursing facility, long-term care facility) following treatment, convey the nature of the infecting organism to the receiving facility. This allows institution of appropriate infection control precautions, if needed.

Deterrence/Prevention

Considering the association of Providencia infections with indwelling devices (eg, urinary catheters, ureteral stent), a careful review of the medical necessity of any such devices is extremely important. The need for such devices should be reviewed periodically, and they should be removed, if possible.

If an indwelling device is required, meticulous care of such devices is important in reducing the likelihood of colonization and infection.

Travelers to developing countries should be counseled to avoid raw or undercooked foods and to drink bottled water. Pre-travel referral to a travel medicine specialist may reduce the risk of travel-related illness.

Providencia species are often resistant to multiple antibiotics. Early identification of such infections and prompt institution of infection-control procedures are important for decreasing the likelihood of spread of the organism among patients.

Kenneth C Earhart, MD is a member of the following medical societies: American College of Physicians, American Society of Tropical Medicine and Hygiene, Infectious Diseases Society of America, and Undersea and Hyperbaric Medical Society

Disclosure: Nothing to disclose.

Leanne B Gasink, MD, MSc Assistant Professor, Department of Medicine and Faculty-Fellow, Center for Clinical Epidemiology and Biostatistics at the University of Pennsylvania School of Medicine; Associate Hospital Epidemiologist, Hospital of the University of Pennsylvania

Joshua S Hawley-Molloy, MD is a member of the following medical societies: American College of Physicians, Armed Forces Infectious Diseases Society, Infectious Diseases Society of America, and Phi Beta Kappa

Ebbing Lautenbach, MD, MPH is a member of the following medical societies: American College of Epidemiology, American College of Physicians, Infectious Diseases Society of America, Society for Epidemiologic Research, and Society for Healthcare Epidemiology of America